New uses for corticotropin releasing factor antagonists

ABSTRACT

A method of treating, preventing or inhibiting a disorder selected from the group consisting of cardiovascular or heart related diseases such as stroke, hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, comprising administering to a mammal, including a human, in need of such treatment a therapeutically effective amount of a compound of the formula  
                 
 
     or pharmaceutically acceptable salt thereof, wherein A, B, D, E, Y, Z, R 3 , R 4 , and R 5  are as defined herein.

BACKGROUND OF THE INVENTION

1. The present invention relates to the treatment of certain conditionsusing a compound of formula I or II, or a pharmaceutically acceptablesalt thereof, as defined below. Specifically, the compounds of formulasI and II, and their pharmaceutically acceptable salts, as defined below,exhibit corticotropin-releasing factor (CRF) antagonist activity and areuseful in the treatment of cardiovascular or heart related diseases suchas hypertension, tachycardia, and congestive heart failure, stroke,osteoporosis, premature birth, psychosocial dwarfism, stress-inducedfever, ulcer, diarrhea, post-operative ileus, and colonichypersensitivity associated with psychopathological disturbance andstress.

2. The compounds of formulas I and II, their pharmaceutically acceptablesalts, and methods of preparing such compounds and salts are referred toin copending PCT international patent application numbers PCT/IB95/00373(filed May 18, 1995) and PCT/IB95/00439 (filed Jun. 6, 1995), both ofwhich designate the United States, and in copending U.S. patentapplications Ser. Nos. 08/448,539 (filed Jun. 14, 1995) and 08/481,413(filed Jun. 15, 1995). PCT international patent application numbersPCT/IB95/00373 and PCT/IB95/00439, and U.S. patent application Ser. Nos.08/448,539 and 08/481,413, referred to above, are incorporated herein byreference in their entirety.

3. The foregoing PCT international patent applications and United Statespatent applications refer to the use of the compounds of formulas I andII in the treatment of illnesses induced or facilitated by corticotropinreleasing factor and in the treatment of anxiety, depression, fatiguesyndrome, gastrointestinal diseases, headache, pain, cancer, immunedysfunction, hemorrhagic stress, drug addiction, drug and alcoholwithdrawal symptoms, fertility problems, stress-induced psychoticepisodes, neurodegenerative diseases such as Alzheimer's disease;irritable bowel syndrome including Crohn's disease, spastic colon andirritable colon; eating disorders such as anorexia nervosa; andinflammatory disorders such as arthritis, asthma and allergies.

4. Other CRF antagonists that can be used to treat the disorders recitedin the method of this invention are referred to in copending PCTinternational patent application number PCT/IB95/00318(filed May 4,1995), which designates the United States, and in copending U.S. patentapplications Ser. Nos. 08/448,534 (filed Jun. 14, 1995) and 08/448,529(filed Jun. 14, 1995). PCT international patent application numberPCT/IB95/00318, and U.S. patent application Ser. Nos. 08/448,534 and08/448,529, referred to above, are incorporated herein by reference intheir entirety.

5. CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and5,063,245 referring to peptides and pyrazolinones, respectively. Theimportance of CRF antagonists is set out in the literature, e.g., asdiscussed in U.S. Pat. No. 5,063,245, which is incorporated herein byreference. A recent outline of the different activities possessed by CRFantagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages425 to 473 (1991), also incorporated herein by reference.

SUMMARY OF THE INVENTION

6. This invention relates to a method of treating a disorder selectedfrom cardiovascular or heart related diseases such as hypertension,tachycardia, and congestive heart failure, osteoporosis, prematurebirth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea,post-operative ileus, and colonic hypersensitivity associated withpsychopathological disturbance and stress, by administering to a mammal,including a human, in need of such treatment a therapeutically effectiveamount of a compound of the formula

7. or a pharmaceutically acceptable salt thereof, wherein

8. the dashed line represents an optional double bond;

9. A is —CR₇ or N;

10. B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₁R₁₂)R₂, —NHCR₁R₁₁R₁R₂, —OCR₁₁R₁R₂,—SCR₁₁R₁R₂, —CR₁₁R₂OR₁, —CR₁₁R₂SR₁, —C(S)R₂, —NHNR₁R₂, —CR₂R₁₁NHR₁ or—C(O)R₂;

11. D is: (i) N or —CR₁₀ when a double bond connects E and D and E is—CR₄; (ii) —CR₁₀ when a double bond connects E and D and E is N; (iii)—CR₈R₉, —CHR₁₀, —C═O, —C═S, —C═NH, or —C═NCH₃ when a single bondconnects E and D;

12. E is —CR₄or N when a double bond connects E and D, and E is —CR₄R₆or—NR₆ when a single bond connects E and D;

13. Y is N or —CH;

14. Z is NH, O, S, —N(C₁-C₂ alkyl) or —CR₁₂R₁₃, wherein R₁₂ and R₁₃ areeach, independently, hydrogen, trifluoromethyl or methyl, or one of R₁₂and R₁₃ is cyano and the other is hydrogen or methyl;

15. R₁ is hydrogen or C₁-C₆ alkyl which is optionally substituted withone or two substituents independently selected from hydroxy, cyano,nitro, fluoro, chloro, bromo, iodo, CF₃, C₁-C₄ alkoxy, —O—CO—(C₁-C₄alkyl), —O—CO—NH(C₁-C₄ alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), (C₁-C₄alkyl)sulfinyl, (C₁-C₄ alkyl)sulfonyl, and (C₁-C₄ alkyl)sulfanyl, andwherein said C₁-C₆ alkyl, C₁-C₄ alkoxy and the C₁-C₄ alkyl moieties inthe foregoing R₁ groups optionally contain one double or triple bond;

16. R₂ is C₁-C₆ alkyl, heteroaryl, aryl, (heteroaryl)C₁-C₄ alkyl or(aryl)C₁-C₄ alkyl wherein said aryl and the aryl moiety of said(aryl)C₁-C₄ alkyl are selected from the group consisting of phenyl andnaphthyl, and said heteroaryl and the heteroaryl moiety of said(heteroaryl)C₁-C₄ alkyl is selected from the group consisting ofthienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,thiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl,and benzoxazolyl; or R² is C₃-C₈ cycloalkyl or (C₃-C₈ cycloalkyl)C₁-C₆alkyl, wherein one or two of the ring carbons of said cycloalkyl havingat least 4 ring members and the cycloalkyl moiety of said (C₃-C₈cycloalkyl)C₁-C₆ alkyl having at least 4 ring members is optionallyreplaced by an oxygen or sulfur atom or by —NR₁₄ wherein R₁₄ is hydrogenor C₁-C₄ alkyl; and wherein each of the foregoing R₂ groups isoptionally substituted by from one to three substituents independentlyselected from chloro, fluoro and C₁-C₄ alkyl, or by one substituentselected from bromo, iodo, cyano, nitro, C₁-C₆ alkoxy, —O—CO—(C₁-C₄alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄ alkyl), (C₁-C₄alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, and (C₁-C₄ alkyl)sulfonyl, andwherein said C₁-C₆ alkyl and the C₁-C₄ alkyl and C₁-C₆ alkyl moieties ofthe foregoing R₂ groups optionally contain one carbon-carbon double ortriple bond;

17. or R¹ and R² of said —NR₁R₂ and said —CR₁R₂R₁₁ are taken together toform a saturated 5 to 8 member ring, wherein said ring optionallycontains one or two carbon-carbon double bonds, and wherein one or twoof the ring carbons is optionally replaced by a heteroatom selected fromO, S and N;

18. R₃ is hydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, iodo, hydroxy,amino, SH, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CH₂OH,—CH₂OCH₃, —O(C₁-C₄ alkyl), (C₁-C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfonyl,or (C₁-C₄ alkyl)sulfinyl, wherein said C₁-C₆ alkyl and the C₁-C₄ alkylmoieties of the foregoing R₃ groups optionally contain one double ortriple bond and are optionally substituted by from one to threesubstituents independently selected from hydroxy, amino, C₁-C₃ alkoxy,—NH(C₁-C₂ alkyl), —N(C₁-C₂)₂, —NHCOCH₃, fluoro, chloro and C₁-C₃thioalkyl;

19. R₄ is hydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, iodo, C₁-C₆alkoxy, formyl, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃,—CH₂CF₃, CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂, —NHCOCH₃,—NHCONHCH₃, (C₁-C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, (C₁-C₄alkyl)sulfonyl, cyano, hydroxy, —CO(C₁-C₄ alkyl), —CHO, or —CO₂(C₁-C₄alkyl), wherein said C₁-C₆ alkyl, C₁-C₆ alkoxy and the C₁-C₄ alkylmoieties of the foregoing R₄ groups optionally contain one double ortriple bond and are optionally substituted with one substituent selectedfrom hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)₂,—CO₂(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), C₁-C₃ alkoxy, (C₁-C₃alkyl)sulfanyl, fluoro, chloro, cyano and nitro;

20. R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9-to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyloptionally contain one or two of O, S or —N—G wherein G is hydrogen,C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl or benzyl, wherein each of the aboveR₅ groups is optionally substituted by from one to three substituentsindependently selected from fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxyand trifluoromethyl, or one substituent selected from bromo, iodo,cyano, nitro, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—CO₂(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₄alkyl), and—SO₂(C₁-C₄alkyl), wherein said C₁-C₄ alkyl and C₁-C₆ alkyl moieties ofthe foregoing R₅ groups optionally contain one double or triple bond andare optionally substituted by one or two substituents independentlyselected from fluoro, chloro, hydroxy, amino, methylamino, dimethylaminoand acetyl;

21. R₆ is hydrogen or C₁-C₆ alkyl, wherein said C₁-C₆ alkyl isoptionally substituted by a single hydroxy, methoxy, ethoxy or fluorogroup;

22. R₇ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, cyano,hydroxy, C₁-C₄ alkoxy, —CO(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), —OCF₃, CF₃,—CH₂OH, —CH₂OCH₃ or —CH₂OCH₂CH₃;

23. R₈ and R₉ are each, independently, hydrogen, hydroxy, methyl, ethyl,methoxy, or ethoxy;

24. or R₈ and R₉ together form an oxo (═O) group;

25. R₁₀ is hydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, iodo, C₁-C₆alkoxy, formyl, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—SO_(n)(C₁-C₄ alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido,wherein said C₁-C₆ alkyl and the C₁-C₄ alkyl moieties of the foregoingR₁₀ groups are optionally substituted by one of hydroxy,trifluoromethyl, amino, carboxy, amido, —NHCO(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄ alkyl), C₁-C₃ alkoxy,C₁-C₃ thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; and,

26. R₁₁ is hydrogen, hydroxy, fluoro, or methoxy.

27. The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight orbranched moieties or combinations thereof.

28. The term “alkoxy”, as used herein, unless otherwise indicated,includes O-alkyl groups wherein “alkyl” is defined above.

29. The term “treatment”, as used herein, unless otherwise indicated,includes the treatment, prevention, or inhibition of any disorderenumerated within the method of the invention.

30. More specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein: B is —NR₁R₂, —NHCHR₁R₂, —CR₁R₂R₁₁, —SCHR₁R₂ or—OCHR₁R₂; R₁ is C₁-C₆ alkyl which is optionally substituted with asingle hydroxy, fluoro or C₁-C₂ alkoxy group and optionally contains onecarbon-carbon double or triple bond; R₂ is benzyl or C₁-C₆ alkyl whichoptionally contains one carbon-carbon double or triple bond, whereinsaid C₁-C₆ alkyl and the phenyl moiety of said benzyl are optionallysubstituted with fluoro, C₁-C₂ alkyl, or C₁-C₂ alkoxy; and R₁ ishydrogen or fluoro.

31. Other more specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein R₂ is (aryl)C₁-C₄ alkyl or (heteroaryl)C₁-C₄alkyl in which said aryl or heteroaryl moiety is phenyl, thienyl,benzofuranyl, furanyl, benzothienyl, thiazolyl, pyridyl orbenzothiazolyl.

32. Other more specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein B is —NR₁R₂ or —CHR₁R₂in which R₁ and R₂ aretaken together with N or CH to form a 5- or 6-membered ring optionallyhaving sulfur, oxygen, or one more nitrogen in said ring, such as apyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl or pyrimidylgroup.

33. Other more specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein B is —NHCHR₁R₂ or —OCHR₁R₂, wherein the CHR₁R₂moiety is a 5- or 6-membered ring which optionally contains one oxygenor sulfur, such as a tetrahydrofuranyl, tetrahydrothiafuranyl orcyclopentanyl group.

34. Other more specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein B is tetrahydrofuranyl, tetrahydrothienyl orthiazolidinyl.

35. Other more specific compounds for use in the method of the inventioninclude compounds of formula I or II, or pharmaceutically acceptablesalts thereof, wherein R₃ is methyl, chloro, or methoxy; R₄ is methyl,—CH₂OH, cyano, trifluoromethoxy, methoxy, trifluoromethyl, chloro,—CO₂CH₃, —CH₂OCH₃, —CH₂Cl, —CH₂F, amino, nitro, hydrogen,methylsulfinyl, methylsulfanyl, methylsulfonyl, or ethyl; and R₅ isphenyl or pyridyl wherein said phenyl or pyridyl is substituted by onesubstituent independently selected from fluoro, chloro, bromo, iodo,C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ hydroxyalkyl, hydroxy, formyl,—CO₂(C₁-C₂alkyl), (amino)C₁-C₂ alkyl, —CO(C₁-C₄alkyl), and C₁-C₆alkyl,wherein said C₁-C₆ alkyl and said C₁-C₄ alkyl are optionally substitutedby a single hydroxy, or fluoro group and optionally contains onecarbon-carbon double or triple bond.

36. For use in the method of the invention, specific compounds offormulas I and II include:

37.4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;

38.2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;

39.2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;

40.3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;

41.2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;

42.4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;

43.2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;

44.2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;

45.4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;

46.[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine;

47.[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;

48.[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)-amine;

49.butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;

50.4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;

51.butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;

52.4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester;

53.[3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;

54.[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;

55.[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine;

56.1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;

57.N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;

58.N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;

59.N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine;

60.[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;

61.[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethyl-propyl)-amine;

62.[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;

63.(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;

64.(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;

65.N-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;

66.[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine;

67.4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;

68.butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;

69.4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;

70.4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;

71.N-butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;

72.(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;

73.[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

74.N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;

75.N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;

76.6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;

77.[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;and

78.6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one.

79. For use in the method of the invention, specific compounds offormula II wherein E and D are connected by a double bond, E is —CR₄, Dis —CR₁₀ or N, Y is N, and A is —CR₇, include:

80.butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethylamine;

81.3,6-dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimethylphenyl)-1H-pyrazo[3,4-b]pyridine;

82.[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl]-(1-methoxymethylpropyl)-amine;

83.4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazo[3,4-b]pyridine;

84.(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-amine;

85.4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;

86.4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;and

87.4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl-4-bromophenyl)-7H-pyrrolo[2,3-b]pyridine.

88. For use in the method of the invention, specific compounds offormula II wherein E and D are connected by a double bond, E is —CR₄,and D, Y and A are N, include:

89.3{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;

90.diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

91.2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-ethanol;

92.dibutyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-amine;

93.butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

94.butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

95.butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

96.di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

97.diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

98.butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

99.butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

100.propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;

101.4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine;

102.2-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4d-]pyrimidin-4-ylamine]-butan-1-ol;

103.[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]-(1-methylpropyl)amine;and

104.4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine.

105. For use in the method of the invention, specific compounds offormula II wherein E and D are connected by a double bond, E is —CR₄, Dis —CR₁₀, and Y and A are N, include:

106.n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

107.di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

108.ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

109.diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

110.n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

111.2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;

112.4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;

113.n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;

114.2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;

115.2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;

116.2-(S)-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;

117.4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;

118.4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;

119.4-(1-ethyl-butyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo-[2,3-d]pyrimidine;

120.[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-methoxymethyl-propyl)-amine;

121.2-[7-(2-bromo-4,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;

122.2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;

123.2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;and

124.2-[7-(2-fluoromethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol.

125. The method of the invention further comprises the treatment ofstroke by administering to a mammal, including a human, in need of suchtreatment a therapeutically effective amount of a compound of formulaII, referred to above, or a pharmaceutically acceptable salt thereof,wherein a double bond connects E and D, D is —CR₁₀ or N, E is —CR₄, andY and A are N. Compounds of formula III, provided below, are thecompounds of formula II wherein a double bond connects E and D, D is—CR₁₀ or N, E is —CR₄, and Y and A are N. The compounds of formula IIIare provided below in the claims and are directed to the treatment ofstroke.

126. Whenever reference is made herein to 3- to 8-membered cycloalkyl or9- to 12-membered bicycloalkyl optionally containing one or two of O, S,or —N—G, it is understood that the oxygen and sulfur atoms are notadjacent to each other in the cycloalkyl or bicycloalkyl ring system.The three membered cycloalkyl optionally contains just one of O, S, or—N—G. An example of a six-membered cycloalkyl having O and NH ismorpholinyl.

127. Whenever R₂ or R₅ is a heterocyclic group, the attachment of thegroup is through a carbon atom.

128. In the compounds of formulas I and II, referred to above, certainaminal or acetal moieties may not be sufficiently stable for use in themethod of the invention. Such unstable compounds may include, forexample, a compound of formula I or II wherein B is —NR₁R₂ and R₁ is—CH(OH)CH₃. Such unstable compounds will be apparent to those skilled inthe art and do not form part of the invention.

129. Formulas I and II, referred to above, are intended to include allstereoisomers (e.g., all geometric and optical isomers) as well asracemates of all individual compounds within the depicted genus.

DETAILED DESCRIPTION OF THE INVENTION

130. The compounds of formulas I and II, and their pharmaceuticallyacceptable salts, are readily prepared. The compounds of formula IIwherein A, D and Y are N, a double bond connects E and D, and E is —CR₄,are prepared by one or more of the synthetic methods referred to in U.S.patent application Ser. No. 08/481,13, referred to above. The compoundsof formula II wherein A and Y are N, a double bond connects E and D, Eis —CR₄, and D is —CF₁₀, are prepared by one or more of the syntheticmethods referred to in U.S. patent application Ser. No. 08/448,539,referred to above. The compounds of formula II wherein A is —CR₇, adouble bond connects E and D, E is —CR₄, D is N or —CF₁₀, and Y is N,are prepared by one or more of the synthetic methods referred to in PCTinternational application number PCT/IB95/00373, referred to above. Theremaining compounds of formula II and the compounds of formula I areprepared by one or more of the synthetic methods referred to in PCTinternational application number PCT/IB95/00439, referred to above.

131. Pharmaceutically acceptable salts of the compounds of formulas Iand II include salts of acidic or basic groups. For example,pharmaceutically acceptable salts include sodium, calcium and potassiumsalts of acidic groups, such as when the R₁₀ substituent is carboxy.Such salts are generally prepared by combining a compound of formula Ior II with one molar equivalent of NaOH or KOH in a suitable solvent.Pharmaceutically acceptable acid addition salts of basic groups, such asamino groups, are formed by reacting the base form of a compound offormula I or II with an appropriate acid. Pharmaceutically acceptablesalts of basic groups include hydrochloride, hydrobromide, sulfate,hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate,acetate, succinate, citrate, tartrate, lactate, mandelate,methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.When the salt is of a monobasic acid (e.g., the hydrochloride, thehydrobromide, the p-toluenesulfonate, the acetate), at least one molarequivalent and usually a molar excess of the acid is employed. However,when such salts as the sulfate, the hemisuccinate, the hydrogenphosphate or the phosphate are desired, the appropriate and exactchemical equivalents of acid will generally be used. The free base andthe acid are usually combined in a co-solvent from which the desiredsalt precipitates, or can be otherwise isolated by concentration oraddition of a non-solvent.

132. In the method of the invention, the compounds of formulas I and II,and their pharmaceutically acceptable salts, can be administered aloneor in combination with pharmaceutically acceptable carriers, in eithersingle or multiple doses. Suitable pharmaceutical carriers include inertsolid diluents or fillers, sterile aqueous solution and various organicsolvents. The pharmaceutical compositions formed by combining the activecompounds and the pharmaceutically acceptable carriers are then readilyadministered in a variety of dosage forms such as tablets, powders,lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thus,for purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type can also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof. Oral administration is generally preferred.However, if the patient is unable to swallow, or oral absorption isotherwise impaired, another route of administration such assuppositories, parenteral (i.m., i.v.), or topical administration willbe appropriate.

133. For parenteral administration, solutions of the active compound insesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution can be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

134. In the method of the invention, the effective dosage for thecompounds of formulas I and II, and their pharmaceutically acceptablesalts, depends on the intended route of administration and other factorssuch as age and weight of the patient, as generally known to aphysician. The dosage also depends on the illness to be treated. Ingeneral, the daily dosage will generally range from about 0.1 to 50mg/kg of the body weight of the patient to be treated. The daily dosagemay be given in a single dose or up to three divided doses. In theprevention of premature birth, the dosage should be administered dailyafter high levels of corticotropin-releasing hormone have been detectedearly in pregnancy and then discontinued just prior to the end of theterm for normal pregnancy.

135. The methods for testing the compounds of formulas I and II, andtheir pharmaceutically acceptable salts, for CRF antagonist activity areas described in Endocrinology, 116, 1653-1659 (1985) and Peptides 10,179-188 (1989) which determine the binding affinity of a test compoundfor a CRF receptor. The binding affinities for the active compounds,expressed as IC₅₀ values, generally range from about 0.2 nanomolar toabout 10 micromolar.

What is claimed is:
 1. A method of treating a disorder selected from thegroup consisting of cardiovascular or heart related diseases includinghypertension, tachycardia, and congestive heart failure, osteoporosis,premature birth, psychosocial dwarfism, stress-induced fever, ulcer,diarrhea, post-operative ileus, and colonic hypersensitivity associatedwith psychopathological disturbance and stress, comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein the dashed linerepresents an optional double bond; A is —CR₇ or N; B is —NR₁R₂,—CR₁R₂R₁, —C(═CR₁, R₁₂)R₂, —NHCR₁₁R₁R₂, —OCR₁₁R₁R₂, —SCR₁₁R₁R₂,—CR₁₁R₂OR₁, —CR₁₁R₂SR₁, —C(S)R₂, —NHNR₁R₂, —CR₂R₁₁NHR₁ or —C(O)R₂; D is:(i) N or —CR₁₀ when a double bond connects E and D and E is —CR₄; (ii)—CR₁₀ when a double bond connects E and D and E is N; or (iii) —CR₈R₉,—CHR₁₀, —C═O, —C═S, —C═NH, or —C═NCH₃ when a single bond connects E andD; E is —CR₄or N when a double bond connects E and D, and E is —CR₄R₆ or—NR₆ when a single bond connects E and D; Y is N or —CH; Z is NH, O, S,—N(C₁-C₂ alkyl) or —CR₁₂R₁₃, wherein R₁₂ and R₁₃ are each,independently, hydrogen, trifluoromethyl or methyl, or one of R₁₂ andR₁₃ is cyano and the other is hydrogen or methyl; R₁ is hydrogen orC₁-C₆ alkyl which is optionally substituted with one or two substituentsindependently selected from hydroxy, cyano, nitro, fluoro, chloro,bromo, iodo, CF₃, C₁-C₄ alkoxy, —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄alkyl)CO(C₁-C₄ alkyl),—NHCO(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄alkyl)(C₁-C₂ alkyl), (C₁-C₄ alkyl)sulfinyl, (C₁-C₄ alkyl)sulfonyl, and(C₁-C₄ alkyl)sulfanyl, and wherein said C₁-C₆ alkyl, C₁-C₄ alkoxy andthe C₁-C₄ alkyl moieties in the foregoing R₁ groups optionally containone double or triple bond; R₂ is C₁-C₆ alkyl, heteroaryl, aryl(heteroaryl)C₁-C₄ alkyl or (aryl)C₁-C₄ alkyl wherein said aryl and thearyl moiety of said (aryl)C₁-C₄ alkyl are selected from the groupconsisting of phenyl and naphthyl, and said heteroaryl and theheteroaryl moiety of said (heteroaryl)C₁-C₄ alkyl is selected from thegroup consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl,and benzoxazolyl; or R² is C₃-C₈ cycloalkyl or (C₃-C₈ cycloalkyl)C₁-C₆alkyl, wherein one or two of the ring carbons of said cycloalkyl havingat least 4 ring members and the cycloalkyl moiety of said (C₃-C₈cycloalkyl)C₁-C₆ alkyl having at least 4 ring members is optionallyreplaced by an oxygen or sulfur atom or by —NR₁₄ wherein R₁₄ is hydrogenor C₁-C₄ alkyl; and wherein each of the foregoing R₂ groups isoptionally substituted by from one to three substituents independentlyselected from chloro, fluoro and C₁-C₄ alkyl, or by one substituentselected from bromo, iodo, cyano, nitro, C₁-C₆ alkoxy,—O—CO—(C₁-C₄alkyl), —O—CO—N(C₁-C₄alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄ alkyl),(C₁-C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, and (C₁-C₄ alkyl)sulfonyl,and wherein said C₁-C₆ alkyl and the C₁-C₄ alkyl and C₁-C₆ alkylmoieties of the foregoing R₂ groups optionally contain one carbon-carbondouble or triple bond; or R¹ and R² of said —NR₁R₂ and said —CR₁R₂R₁₁are taken together to form a saturated 5 to 8 member ring, wherein saidring optionally contains one or two carbon-carbon double bonds, andwherein one or two of the ring carbons is optionally replaced by aheteroatom selected from O, S and N; R₃ is hydrogen, C₁-C₆ alkyl,fluoro, chloro, bromo, iodo, hydroxy, amino, SH, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CH₂OH, —CH₂OCH₃, —O(C₁-C₄ alkyl), (C₁- C₄alkyl)sulfanyl, (C₁-C₄ alkyl)sulfonyl, or (C₁-C₄ alkyl)sulfinyl, whereinsaid C₁-C₆ alkyl and the C₁-C₄ alkyl moieties of the foregoing R₃ groupsoptionally contain one double or triple bond and are optionallysubstituted by from one to three substituents independently selectedfrom hydroxy, amino, C₁-C₃ alkoxy, —NH(C₁-C₂ alkyl), —N(C₁-C₂)₂,—NHCOCH₃, fluoro, chloro and C₁-C₃ thioalkyl; R₄ is hydrogen, C₁-C₆alkyl, fluoro, chloro, bromo, iodo, C₁-C₆ alkoxy, formyl,trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂CF₃, CF₃,amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂, —NHCOCH₃, —NHCONHCH₃, (C₁-C₄alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, (C₁-C₄alkyl)sulfonyl, cyano,hydroxy, —CO(C₁-C₄alkyl), —CHO, or —CO₂(C₁- C₄ alkyl), wherein saidC₁-C₆ alkyl, C₁-C₆ alkoxy and the C₁-C₄ alkyl moieties of the foregoingR₄ groups optionally contain one double or triple bond and areoptionally substituted with one substituent selected from hydroxy,amino, —NHCOCH₃, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)₂, —CO₂(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), C₁-C₃ alkoxy, (C₁-C₃ alkyl)sulfanyl, fluoro, chloro,cyano and nitro; R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9-to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyloptionally contain one or two of O, S or —N—G wherein G is hydrogen,C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl or benzyl, wherein each of the aboveR₅ groups is optionally substituted by from one to three substituentsindependently selected from fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxyand trifluoromethyl, or one substituent selected from bromo, iodo,cyano, nitro, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—CO₂(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), and—SO₂(C₁-C₄ alkyl), wherein said C₁-C₄ alkyl and C₁-C₆ alkyl moieties ofthe foregoing R₅ groups optionally contain one double or triple bond andare optionally substituted by one or two substituents independentlyselected from fluoro, chloro, hydroxy, amino, methylamino, dimethylaminoand acetyl; R₆ is hydrogen or C₁-C₆ alkyl, wherein said C₁-C₆ alkyl isoptionally substituted by a single hydroxy, methoxy, ethoxy or fluorogroup; R₇ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, cyano,hydroxy, C₁-C₄ alkoxy, —CO(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl), —OCF₃, CF₃,—CH₂OH, —CH₂OCH₃ or —CH₂OCH₂CH₃; R₈ and R₉ are each, independently,hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy; or R₈ and R₉together form an oxo (═O) group; R₁₀ is hydrogen, C₁-C₆ alkyl, fluoro,chloro, bromo, iodo, C₁-C₆ alkoxy, formyl, amino, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO_(n)(C₁-C₄ alkyl), wherein n is 0, 1 or2, cyano, carboxy, or amido, wherein said C₁-C₆ alkyl and the C₁-C₄alkyl moieties of the foregoing R₁₀ groups are optionally substituted byone of hydroxy, trifluoromethyl, amino, carboxy, amido, —NHCO(C₁-C₄alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄alkyl), C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, bromo, chloro, iodo,cyano or nitro; and, R₁₁ is hydrogen, hydroxy, fluoro, or methoxy. 2.The method of claim 1 wherein B is —NR₁R₂, —NHCHR₁R₂, —CR₁R₂R₁₁,—SCHR₁R₂ or —OCHR₁R₂; R₁ is C₁-C₆ alkyl which is optionally substitutedwith a single hydroxy, fluoro or C₁-C₂ alkoxy group and optionallycontains one carbon-carbon double or triple bond; R₂ is benzyl or C₁-C₆alkyl which optionally contains one carbon-carbon double or triple bond,wherein said C₁-C₆ alkyl and the phenyl moiety of said benzyl areoptionally substituted with fluoro, C₁-C₂ alkyl, or C₁-C₂ alkoxy; andR₁₁ is hydrogen or fluoro.
 3. The method of claim 1 wherein R₂ is(aryl)C₁-C₄ alkyl or (heteroaryl)C₁-C₄ alkyl in which said aryl orheteroaryl moiety is phenyl, thienyl, benzofuranyl, furanyl,benzothienyl, thiazolyl, pyridyl or benzothiazolyl.
 4. The method ofclaim 1 wherein B is NR₁R₂ or CHR₁R₂ in which R₁ and R₂ are takentogether with N or CH to form a 5- or 6-membered ring optionally havingsulfur, oxygen, or, where B is NR₁R₂, one more nitrogen in said ring. 5.The method of claim 1 wherein B is —NHCHR₁R₂ or —OCHR₁R₂, wherein theCHR₁R₂ moiety is a 5- or 6-membered ring which optionally contains oneoxygen or sulfur.
 6. The method of claim 5 wherein B istetrahydrofuranyl, tetrahydrothiafuranyl or cyclopentanyl.
 7. The methodof claim 5 wherein B is tetrahydrofuranyl, tetrahydrothienyl orthiazolidinyl.
 8. The method of claim 1 wherein R₃ is methyl, chloro, ormethoxy; R₄ is methyl, —CH₂OH, cyano, trifluoromethoxy, methoxy,trifluoromethyl, chloro, —CO₂CH₃, —CH₂OCH₃, —CH₂Cl, —CH₂F, amino ornitro; R₆ is hydrogen, methylsulfinyl, methylsulfanyl, methylsulfonyl,or ethyl; and R₅ is phenyl or pyridyl wherein said phenyl or pyridyl issubstituted by one substituent independently selected from fluoro,chloro, bromo, iodo, C₁-C₄ alkoxy, trifluoromethyl, C₁-C₃ hydroxyalkyl,—CO₂(C₁-C₂ alkyl), (amino)C₁-C₂ alkyl, —CO(C₁-C₄ alkyl), and C₁-C₆alkyl, wherein said C₁-C₆ alkyl and said C₁-C₄ alkyl are optionallysubstituted by a single hydroxy, or fluoro group and optionally containsone carbon-carbon double or triple bond.
 9. The method of claim 1wherein the compound of formula I or II is selected from the groupconsisting of:4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;4-(1-methoxymethyl-propoxy)-3,6-dimethyl-pyridine;[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;[2,5-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine;butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester;[3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine;1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine;[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethyl-propyl)-amine;[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;N-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine;4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;N-butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one,and pharmaceutically acceptable salts of the foregoing compounds. 10.The method of claim 1 wherein said compound is a compound of formula IIin which E and D are connected by a double bond, E is —CR₄, D is —CR₁₀or N, Y is N, and A is —CR₇.
 11. The method of claim 10 wherein saidcompound is selected from the group consisting of:butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethylamine;3,6-dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl]-(1-methoxymethylpropyl)-amine;4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine;(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-amine;4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl-4-bromophenyl)-7H-pyrrolo[2,3-b]pyridine,and pharmaceutically acceptable salts of the foregoing compounds. 12.The method of claim 1 wherein said compound is a compound of formula IIin which E and D are connected by a double bond, E is —CR₄, and D, Y andA are N.
 13. The method of claim 12 wherein said compound is selectedfrom the group consisting of:3-{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-ethanol;dibutyl-{6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-amine;butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine;2-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine]-butan-1-ol;[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]-(1-methylpropyl)amine;4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine,and pharmaceutically acceptable salts of the foregoing compounds. 14.The method of claim 1 wherein said compound is a compound of formula IIin which E and D are connected by a double bond, E is —CR₄, D is —CR₁₀,and Y and A are N.
 15. The method of claim 14 wherein said compound isselected from the group consisting of:n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;2-(S)-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;4-(1-ethyl-butyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo-[2,3-d]pyrimidine;[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-methoxymethyl-propyl)-amine;2-[7-(2-bromo-4,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;2-[7-(2-fluoromethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol,and pharmaceutically acceptable salts of the foregoing compounds.
 16. Amethod of treating stroke comprising administering to a mammal in needof such treatment a therapeutically effective amount of a compound ofthe formula

or a pharmaceutically acceptable salt thereof, wherein B is —NR₁R₂,—CR₁R₂R₁₁, —C(═CR₁R₁₂)R₂, —NHCR₁₁R₁R₂, —OCR₁₁R₁R₂, —SCR₁₁R₁R₂,—CR₁₁R₂OR₁, —CR₁₁R₂SR₁, —C(S)R₂, —NHNR₁R₂, —CR₂R₁₁NHR, or —C(O)R₂; D isN or —CR₁₀; R₁ is hydrogen or C₁-C₆ alkyl which is optionallysubstituted with one or two substituents independently selected fromhydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF₃, C₁-C₄ alkoxy,—O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl),—N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), (C₁-C₄alkyl)sulfinyl, (C₁-C₄ alkyl)sulfonyl, and (C₁-C₄ alkyl)sulfanyl, andwherein said C₁-C₆ alkyl, C₁-C₄ alkoxy and the C₁-C₄ alkyl moieties inthe foregoing R₁ groups optionally contain one double or triple bond; R₂is C₁-C₆ alkyl, heteroaryl, aryl, (heteroaryl)C₁-C₄ alkyl or (aryl)C₁-C₄alkyl wherein said aryl and the aryl moiety of said (aryl)C₁-C₄ alkylare selected from the group consisting of phenyl and naphthyl, and saidheteroaryl and the heteroaryl moiety of said (heteroaryl)C₁-C₄ alkyl isselected from thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl,and benzoxazolyl; or R² is C₃- C₈ cycloalkyl or (C₃-C₈ cycloalkyl)C₁-C₆alkyl, wherein one or two of the ring carbons of said cycloalkyl havingat least 4 ring members and the cycloalkyl moiety of said (C₃- C₈cycloalkyl)C₁-C₆ alkyl having at least 4 ring members is optionallyreplaced by an oxygen or sulfur atom or by —NR₁₄ wherein R₁₄ is hydrogenor C₁-C₄ alkyl; and wherein each of the foregoing R₂ groups isoptionally substituted by from one to three substituents independentlyselected from chloro, fluoro and C₁-C₄ alkyl, or by one substituentselected from bromo, iodo, cyano, nitro, C₁-C₆ alkoxy,—O—CO—(C₁-C₄alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄alkyl), (C₁-C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, and (C₁-C₄alkyl)sulfonyl, and wherein said C₁-C₆ alkyl and the C₁-C₄ alkyl andC₁-C₆ alkyl moieties of the foregoing R₂ groups optionally contain onecarbon-carbon double or triple bond; or R¹ and R² of said —NR₁R₂ andsaid —CR₁R₂R₁₁ are taken together to form a saturated 5 to 8 memberring, wherein said ring optionally contains one or two carbon-carbondouble bonds, and wherein one or two of the ring carbons is optionallyreplaced by a heteroatom selected from O, S and N; R₃ is hydrogen, C₁-C₆alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CH₂OH, —CH₂OCH₃, —O(C₁-C₄ alkyl),(C₁- C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfonyl, or (C₁-C₄ alkyl)sulfinyl,wherein said C₁-C₆ alkyl and the C₁-C₄ alkyl moieties of the foregoingR₃ groups optionally contain one double or triple bond and areoptionally substituted by from one to three substituents independentlyselected from hydroxy, amino, C₁-C₃ alkoxy, —NH(C₁-C₂ alkyl),—N(C₁-C₂)₂, —NHCOCH₃, fluoro, chloro and C₁-C₃ thioalkyl; R₄ ishydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, iodo, C₁-C₆ alkoxy,formyl, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂CF₃,CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂, —NHCOCH₃, —NHCONHCH₃,(C₁-C₄ alkyl)sulfanyl, (C₁-C₄ alkyl)sulfinyl, (C₁-C₄alkyl)sulfonyl,cyano, hydroxy, —CO(C₁-C₄alkyl), —CHO, or —CO₂(C₁-C₄ alkyl), whereinsaid C₁-C₆ alkyl, C₁-C₆ alkoxy and the C₁-C₄ alkyl moieties of theforegoing R₄ groups optionally contain one double or triple bond and areoptionally substituted with one substituent selected from hydroxy,amino, —NHCOCH₃, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)₂, —CO₂(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), C₁-C₃ alkoxy, (C₁-C₃ alkyl)sulfanyl, fluoro, chloro,cyano and nitro; R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9-to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyloptionally contain one or two of O, S or —N—G wherein G is hydrogen,C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl or benzyl, wherein each of the aboveR₅ groups is optionally substituted by from one to three substituentsindependently selected from fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxyand trifluoromethyl, or one substituent selected from bromo, iodo,cyano, nitro, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—CO₂(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), and—SO₂(C₁-C₄alkyl), wherein said C₁-C₄ alkyl and C₁-C₆ alkyl moieties ofthe foregoing R₅ groups optionally contain one double or triple bond andare optionally substituted by one or two substituents independentlyselected from fluoro, chloro, hydroxy, amino, methylamino, dimethylaminoand acetyl; R₁₀ is hydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, iodo,C₁-C₆ alkoxy, formyl, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂alkyl), —SO (C₁-C₄ alkyl), wherein n is 0, 1 or 2, cyano, carboxy, oramido, wherein said C₁-C₆ alkyl and the C₁-C₄ alkyl moieties of theforegoing R₁₀ groups are optionally substituted by one of hydroxy,trifluoromethyl, amino, carboxy, amido, —NHCO(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —CO₂(C₁-C₄ alkyl), C₁-C₃ alkoxy,C₁-C₃ thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; and, R₁₁is hydrogen, hydroxy, fluoro, or methoxy.